Structural birth defects are a devastating cause of fetal, perinatal, and pediatric loss and contribute to a great deal of long term morbidity. Some common congenital defects may be amenable to new treatment strategies that start in the fetus as early treatment may modulate later outcomes. Although treatment strategies including fetal surgery have made huge advances over the past decade, a major limitation continues to be the lack of suitable and readily available large animal models to develop and test therapy. This proposal seeks to identify naturally occurring genetic swine models for specific birth defects for which large animal models are needed. In a small pilot screen, we have shown that this approach is feasible and likely to be successful as a potential obstructive uropathy phenotype has already been discovered in a related population of swine. In Aim 1, we propose to conduct a large scale screen in swine to identify populations with recurrence of specific structural birth defects. The birth defects that we propose to identify have previously been reported in swine and include congenital diaphragmatic hernia (CDH), congenital heart disease, myelomeningocele, obstructive uropathy, and orofacial clefting. In Aim 2, populations identified with congenital defects will be used to determine whether the specific phenotypes would make suitable models for human disease research. The heritability and patterns of inheritance will also be determined, and DNA will be extracted and stored from affected populations for future genetic studies. The long term goal is for the specific identified models with high heritability and high relevance to human disease to be expanded for distribution to the research community. The availability of these tools would greatly enhance the translation of experimental therapies to the human and have a direct and rapid impact on human disease. PUBLIC HEALTH RELEVANCE: In this proposal, we will screen piglets that die of "natural causes" to determine if specific herds are carrying genetic birth defects that could serve as important models of human disease. The birth defects that will be screened are: congenital diaphragmatic hernia (CDH), congenital heart disease, myelomeningocele, obstructive uropathy, and orofacial clefting. Our hope is that once they are identified, those affected pig families (carriers) could then be used to provide the research community with important models to test new therapies for the human fetus or neonate. This would potentially have a huge and rapid impact on treatment for these disorders.